PROJECT SUMMARY Working memory (WM) is one of the core components of executive functions essential for everyday life activities. It is one of the central cognitive constructs included in the NIMH Research Domains Criteria (RDoC) that depends critically on sustained active maintenance in the prefrontal cortex which interacts with parietal regions in a task dependent manner. Accumulating evidence suggest that WM deficits present in a wide range of brain disorders including attention deficit hyperactivity disorder (ADHD). Without early intervention, WM deficits will continue to reduce the likelihood of academic and occupational success. In line with NIMH's emphasis on developing personalized interventions that focus on operationally defined functional domains of mental disorders, particularly intervention targets related to RDoC constructs, we are proposing a novel intervention to enhance WM by probing the individualized neural systems underlying WM. Particularly, the proposed intervention integrates computerized WM training with real-time neuromonitoring and neurofeedback to guide the intervention through reinforcement of a strategy that maximizes the engagement of the target WM network. We will particularly focus on the frontal-parietal circuit (target) which is the core system underlying WM. We will test the proposed intervention on children with ADHD with WM deficits, given a wealth of data demonstrating prevalence of WM impairment in this population that is often associated with hypoactivation in the frontal and parietal circuits indicated by fMRI and fNIRS studies. In the R61 proof-of-concept phase, we will assess target engagement, effective dose and feasibility. Sixty children with ADHD with WM deficits will be randomized to treatment (N = 30) or control (N = 30). Both groups will be assessed using a set of neuroimaging, clinical and behavioral assessments. Particularly, we will test if the intervention results in normalized activity (reduced hypoactivity) in the frontal-parietal network and improved WM performance during N-back task. If the intervention results in improvement in target engagement and WM performance based on the proposed criteria, we will advance to the R33 phase to replicate and validate the effects of the optimal dose of the proposed intervention, versus an active comparison intervention, in a larger sample of children with ADHD (N = 100) with WM deficits. We will also test if enhanced activity in the frontal-parietal network is associated with improvement in BRIEF WM scale (clinical outcome) and N-back performance (functional outcome). Finally, we will assess retention, adherence, satisfaction and acceptability of randomization and will develop and standardize the protocols for a larger trial if the milestones for (a) target engagement, (b) association between target engagement and clinical WM outcomes, and (c) feasibility are met. Validation of the proposed approach will provide a foundation for developing personalized, pathology- focused, cross-diagnostic interventions and could significantly enhance patient outcomes and public health.